The cellular receptor for urokinase (uPAR, CD87) plays multiple functions in cell migration, cell adhesion, pericellular proteolysis and tissue remodeling [Blasi, 1997]. uPAR is expressed by most leukocytes including monocytes, macrophages, neutrophils and platelets. uPAR is an activation antigen in monocytes and T cells [Min, 1992][Nykjaer, 1994] and T-cells from HIV-1 infected individuals express elevated levels of uPAR [Nykjaer, 1994]. HIV-1 infection of leukocytes in vitro causes up-regulation of uPAR cell surface expression in a process which appear to be coordinated temporally with the onset of viral replication [Frank, 1996], [Speth, 1998].
uPAR may be shed from the cell surface generating a soluble form of the receptor (suPAR) lacking the GPI-anchor. The shedding mechanism is poorly understood but may occur by GPI-specific phospholipase D catalyzed hydrolytic cleavage of the GPI-anchor (Wilhelm, 1999). Soluble forms of uPAR (suPAR) has been identified in cell culture supernatants and in diverse biological fluids such as tumor ascites, cystic fluid, serum, plasma and recently also in urine [Pedersen, 1993], [Rønne, 1995], [Stephens, 1997], [Sier, 1998], [Chavakis, 1998], [Stephens, 1999], [Wahlberg, 1998], [Sier, 1999].
Serum, plasma and urine levels of suPAR are elevated in patients suffering from different types of cancer [Stephens, 1997], [Sier, 1998], [Stephens, 1999], [Sier, 1998], the paroxysmal nocturnal hemoglobinuria syndrome (PNH) syndrome [Rønne, 1995], [Ninomiya, 1997], and in rheumatoid arthritis patients [Slot, 1999]. The plasma level of suPAR is furthermore a prognostic marker for overall survival in patients suffering from ovarian and colorectal cancer [Sier, 1998], [Stephens, 1999] and for the response to therapy in leukemia [Mustjoki, 1999].
The cellular origin of circulating suPAR is not known. Many, if not all, cells which express uPAR also shed soluble forms of the receptor when cultured in vitro. The source of excess serum suPAR in cancer patients has been suggested to derive from the cancer cells and/or tumor-infiltrating macrophages as these cells often express high levels of uPAR [Stephens, 1997] and experiments using xenografted mice carrying human tumors have indeed demonstrated that the tumor tissue does release suPAR to the circulation and urine [Holst-Hansen, 1999].
Persons infected with HIV-1 probably represents the single most well medically monitored group of patients ever in history. Despite these very intensive studies only few prognostic markers, providing long-term predictions of clinical outcome, have proven strong enough to obtain broad clinical acceptance. Currently used prognostic markers for disease progression in untreated HIV-1 infected patients are essentially restricted to the blood concentration of CD4 positive lymphocytes (the CD4 cell count), the plasma level of HIV-1 RNA (the viral load), and the age of the patient.
CD4+ T cell counting is a general marker of immune deficiency, whereas HIV viral load provides direct information about viral replication. Although these two parameters are based on different approaches, they both provide information about the expected clinical outcome and prognosis of the patient. In specific cases one of the two assays is more useful than the other, which is the reason that both markers are found to be independent parameters in multivariate analysis. Hence, preferably both markers should be used together. Other potential prognostic parameters like age of the patients or β2 microglobulin level give additional information, but usually their significance decrease if they are used in multivariate analyses together with CD4+ or HIV viral load.
After the introduction of highly active anti-retroviral therapy (HAART) therapy, viral load is dramatically reduced and CD4 T cell counts become stable, which decreases the clinical use of these markers for prognostic/diagnostic purposes. Hence, there is a strong need for novel markers useful for monitoring patients in HAART therapy.
Measurements of CD4 cell counts and HIV-1 viral load are expensive and require equipment (flow-cytometers and PCR-machines) which is unlikely to be affordable for wide use in developing countries such as Uganda, Rwanda and Namibia. In these countries, around 30% of individuals between the age of 20 and 49 years are infected (October 1999 data).